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Cited by 56Hearing, Cochlea, Tinnitus, GeneticsCellular Mechanics and InteractionsGenetic and Kidney Cyst Diseases

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Structural basis for tunable control of actin dynamics by myosin-15 in mechanosensory stereocilia

Open access
Gong, Rui, Jiang, Fangfang, Moreland, Zane G., Reynolds, Matthew J., de los Reyes, Santiago Espinosa, Gurel, Pinar, Shams, Arik, Heidings, James B., Bowl, Michael R., Bird, Jonathan E., Alushin, Gregory M.·2022·Science Advances
DOI 10.1126/sciadv.abl4733PMC PMC9299544

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Abstract

The motor protein myosin-15 is necessary for the development and maintenance of mechanosensory stereocilia, and mutations in myosin-15 cause hereditary deafness. In addition to transporting actin regulatory machinery to stereocilia tips, myosin-15 directly nucleates actin filament (“F-actin”) assembly, which is disrupted by a progressive hearing loss mutation (p.D1647G, “ jordan ”). Here, we present cryo–electron microscopy structures of myosin-15 bound to F-actin, providing a framework for interpreting the impacts of deafness mutations on motor activity and actin nucleation. Rigor myosin-15 evokes conformational changes in F-actin yet maintains flexibility in actin’s D-loop, which mediates inter-subunit contacts, while the jordan mutant locks the D-loop in a single conformation. Adenosine diphosphate–bound myosin-15 also locks the D-loop, which correspondingly blunts actin-polymerization stimulation. We propose myosin-15 enhances polymerization by bridging actin protomers, regulating nucleation efficiency by modulating actin’s structural plasticity in a myosin nucleotide state–dependent manner. This tunable regulation of actin polymerization could be harnessed to precisely control stereocilium height.

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Metadata

Authors
Gong, R., Jiang, F., Moreland, Z. G., Reynolds, M. J., de los Reyes, S. E., Gurel, P., Shams, A., Heidings, J. B., Bowl, M. R., Bird, J. E., & Alushin, G. M.
Affiliations
  • Rockefeller University (US)
  • University of Florida (US)
  • Laboratory of Structural Biophysics and Mechanobiology, The Rockefeller University, New York, NY, USA.
  • National Institutes of Health (US)
  • Mary Lyon Centre at MRC Harwell (GB)
Corresponding author
  • Bird, Jonathan E.
  • Alushin, Gregory M.
ORCID
Venue
Science Advances
Publisher
American Association for the Advancement of Science (AAAS)
Published
2022-07-22
Volume
8
Issue
29
Pages
eabl4733-eabl4733
ISSN
2375-2548 (ISSN-L)
DOI
10.1126/sciadv.abl4733
PMC
PMC9299544
OpenAlex
W4285987596
Cited by
56
References
1
Citations by year
2026: 9 · 2025: 14 · 2024: 12 · 2023: 11 · 2022: 8
FWCI
6.75
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Science Advances (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion)
Funders
  • National Institutes of Health (DP5OD017885)
  • Medical Research Council (MR/X004597/1)
  • National Heart, Lung, and Blood Institute
  • National Institute on Deafness and Other Communication Disorders (R01DC018827, T32DC000039, Z01DC000039)
  • National Institute of General Medical Sciences (R01GM141044)
Topics
  • Life Sciences › Neuroscience › Sensory Systems › Hearing, Cochlea, Tinnitus, Genetics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
Keywords
actin nucleation, F-actin polymerization, stereocilia, mechanosensory hair cells, hereditary hearing loss, cryo-EM structure

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